Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1

Abstract

Objectives: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. Design: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). Methods: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4 + T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4 + T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). Results: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4 + T-cell count increases were comparable across subgroups. Participants with baseline CD4 + T-cell counts less than 20 cells/μl had a mean increase of 240 cells/μl. In the safety population, more participants with baseline CD4 + T-cell counts less than 20 vs. at least 200 cells/μl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. Conclusion: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

Fostemsavir in Heavily Treatment-Experienced Individuals Living with HIV-1: Insights from the Phase 3 BRIGHTE Study

“…The safety profile of fostemsavir-based regimens in BRIGHTE participants was consistent with previous reports from clinical trials in participants with multidrug-resistant HIV-1 [2, 4,14,16,17,34]. Most (347/370; 94%) participants reported at least one adverse event (AE), most commonly diarrhea, nausea, upper respiratory tract infection, and headache [3,4]. Most AEs were mild or moderate in severity, self-limited, and resolved without interruption of study drug [4].…”

“…In the Randomized Cohort, CD4 + T-cell increases were generally consistent across subgroups based on demographics and disease characteristics [3]. Notably, participants who were the most immunosuppressed at baseline (CD4 + T-cell count <20 cells/mm 3 ) achieved the greatest increases in CD4 + T-cell count at Week 96 (mean increase of 240 cells/mm 3 ) [4].…”

“…In BRIGHTE, the absolute number of Randomized Cohort participants classified as virologic responders in the Snapshot ITT-E analysis went up by 19 from Week 24 (n=144) to Week 96 (n=163). This unique finding reflects the fact that 63 Randomized Cohort participants first achieved virologic response after Week 24 (n=44) or Week 48 (n=29) [3]. When we looked at the observed analysis, in which participants with missing data are excluded and changes in OBT are not counted as failures, this unprecedented efficacy trend was especially pronounced in the Randomized Cohort with virologic response rates increasing from 57% (141/246) at Week 24 to 62% (145/233) at Week 48 and 79% (170/214) at Week 96.…”

“…Most AEs were mild or moderate in severity, self-limited, and resolved without interruption of study drug [4]. There were few drug-related serious AEs (12/370; 3%) and AEs leading to discontinuation (26/370; 7%) [3]. Most severe AEs (grade 3-4 AEs, serious AEs, and deaths) were related to complications of advanced HIV disease and acute infections and occurred disproportionately in participants who were the most immunocompromised at baseline and in Non-randomized Cohort participants [3,4].…”

“…Fostemsavir (Rukobia™, ViiV Healthcare, Research Triangle Park, NC), a prodrug of the first-in-class attachment inhibitor temsavir, was developed to provide a much-needed new therapeutic option for heavily treatment-experienced (HTE) people living with HIV-1 (PLWH) who are unable to form a suppressive regimen from remaining viable antiretroviral (ARV) agents because of multidrug resistance, contraindications, prior intolerance, or other safety considerations [1][2][3][4]. Effective treatment for this vulnerable population can be complicated by other challenges in addition to multidrug resistance, including low CD4+ T-cell counts, comorbidities, psychosocial factors, and non-adherence to complex regimens [4][5][6][7][8][9].…”